Epidermal growth factor prevents thallium(I)- and thallium(III)-mediated rat pheochromocytoma (PC12) cell apoptosis

Abstract

We have reported recently that the proliferation of PC12 cells exposed to micromolar concentrations of Tl(I) or Tl(III) has different outcomes, depending on the absence (EGF cells) or the presence (EGF cells) of epidermal growth factor (EGF) added to the media. In the current work, we investigated whether EGF supplementation could also modulate the extent of Tl(I)- or Tl(III)-induced cell apoptosis. Tl(I) and Tl(III) (25-100 μM) decreased cell viability in EGF but not in EGF cells. In EGF cells, Tl(I) decreased mitochondrial potential, enhanced HO generation, and activated mitochondrial-dependent apoptosis. In addition, Tl(III) increased nitric oxide production and caused a misbalance between the anti- and pro-apoptotic members of Bcl-2 family. Tl(I) increased ERK1/2, JNK, p38, and p53 phosphorylation in EGF cells. In these cells, Tl(III) did not affect ERK1/2 and JNK phosphorylation but increased p53 phosphorylation that was related to the promotion of cell senescence. In addition, this cation significantly activated p38 in both EGF and EGF cells. The specific inhibition of ERK1/2, JNK, p38, or p53 abolished Tl(I)-mediated EGF cell apoptosis. Only when p38 activity was inhibited, Tl(III)-mediated apoptosis was prevented in EGF and EGF cells. Together, current results indicate that EGF partially prevents the noxious effects of Tl by preventing the sustained activation of MAPKs signaling cascade that lead cells to apoptosis and point to p38 as a key mediator of Tl(III)-induced PC12 cell apoptosis.

Mitochondrial Oxidative Stress Is the General Reason for Apoptosis Induced by Different-Valence Heavy Metals in Cells and Mitochondria

“…Apoptosis, membrane integrity disruption, MPTP opening, Na + /K + -ATPase inhibition, glutathione depletion, ∆Ψ mito decline, cell viability loss, cytochrome c release, membrane fluidity rise, ATP depletion from mitochondria, and an increase in lipid peroxidation, ROS production, and H 2 O 2 synthesis were induced by Tl + in experiments with isolated rat hepatocytes, isolated synaptosomal mitochondrial fractions of P2, PC12, and HN9.10e neuronal cells, C6 glioma and Jurkat T cells [9,115,[133][134][135][136][137][138][139][140][141][142]. Tl + -induced apoptosis in PC12 cells was later shown to be associated with the activation of the MAPK-dependent cascade of protein kinases: extracellular signal-regulated kinase (ERK)1/2, c-jun N-terminal kinase (JNK), p38, and p53 of the Bcl-2 family [138]. Experiments with TlCl-treated rat hepatocytes found increased cytoplasmic concentrations of Ca 2+ and Na + but decreased K + concentrations [22].…”

The Impact of Thallium Exposure in Public Health and Molecular Toxicology: A Comprehensive Review

“…Furthermore, it was discovered that the extent of cell apoptosis induced by Tl (I) and Tl (III) varies in the presence of epidermal growth factor (EGF). The results suggest that EGF partially mitigates toxicity by inhibiting the sustained activation of the MAPK signaling cascade, and indicate that p38 plays a crucial role as a mediator in Tl (III)-induced apoptosis in PC12 cells [64]. Using the HN9.10e cell line, which is a fusion of mouse hippocampal neuroblasts and neuroblastoma cells, it was observed that Tl (I) caused neurite shortening, loss of matrix adhesion, and an increase in cytoplasmic calcium.…”

Efficient removal of thallium from flow gas using manganite‐based catalysts by gas–solid‐phase catalytic oxidation at low temperature

“…Geologically, Tl(I) ions are found mostly in potassium-based ores and, when ingested, are handled similarly to K + by ion pumps to living cells. [12,13] Therefore, Tl(I) compounds have median lethal dose of ≥10 mg kg −1 to humans, making them more poisonous than any other Tl(III) compound. [14,15] Coal, smelting, and incineration industry, such as coal-fired power plant facilities, municipal solid waste incineration, nonferrous or ferrous smelting, or hazardous waste combustion, are regarded as the major anthropogenic sources of Tl to the air environment.…”

“…Geologically, Tl(I) ions are found mostly in potassium‐based ores and, when ingested, are handled similarly to K + by ion pumps to living cells. [ 12,13 ] Therefore, Tl(I) compounds have median lethal dose of ≥10 mg kg −1 to humans, making them more poisonous than any other Tl(III) compound. [ 14,15 ]…”